Abstract 4456: Aurora-A is a downstream target of RAS and forms a positive feedback regulation loop with NF-κB in non-small cell lung cancer

Abstract

Abstract Previous studies have shown that inhibition of Aurora-A reduces mutant RAS oncogenic activity and that both Aurora-A and RAS activate NF-κB pathway through phosphorylation of IkBa and upregulation of GSKa, respectively. Here we show that Aurora-A expression and kinase activity are regulated by activating mutation of KRAS. Blockage of NF-κB by IκB-S32/36A abrogated KRAS-induced Aurora-A expression and kinase activity. Furthermore, we demonstrated that NF-κB directly bound to Aurora-A promoter and induces Aurora-A transcription. In addition, depletion of Aurora-A by siRNA and pharmacological inhibitor MLN8237 suppresses RAS-induced NF-κB activity and selectively induces cell death in KRAS mutant NSCLC cells. We also show that Aurora-A is induced by nicotine and is frequently overexpressed in NSCLCs. Overexpression of Aurora-A is associated with tobacco smoke and poor prognosis in lung adenocarcinoma but not squamous lung cancer. These data suggest that Aurora-A is regulated by RAS through NF-κB and that the feedback regulation loop between Aurora-A and NF-κB could play a pivotal role in NSCLC. Citation Format: Donghwa Kim, Masayuki Kanai, Xiangqian Zheng, Dali Zheng, Domenico Coppola, Jin Q. Cheng. Aurora-A is a downstream target of RAS and forms a positive feedback regulation loop with NF-κB in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4456. doi:10.1158/1538-7445.AM2014-4456